N-propiophenone-norephedrines and salts thereof

ABSTRACT

Amino ketones of the formula   WHEREIN: R1 is selected from the group consisting of -Br, lower alkyl, NH2 and trifluoromethyl; R2 and R3 are selected from the group consisting of -H, -C1, Br, lower alkyl, -OH and lower alkoxy; R4 is -H, methyl or ethyl; R5 is -H or lower alkyl; R6 is -H or methyl; R7 is -H or -OH and AT LEAST ONE OF R8 and R9 is -OH and the other is -H, -OH, halogen, lower alkyl or lower alkoxy and certain amino ketones of said formula wherein R4, R5, R8 and R9 are -H, R6 is methyl and R7 is -OH and their pharmacologically acceptable acid addition salts and quaternary ammonium salts, such compounds having pharmaceutical activity in improving the heart function.

United States atet [72] Inventor Kurt Thiele Frankfurt am Main, Germany[21] Appl. No. 749,555 [22] Filed July 1, 1968 [45] Patented Nov. 16,1971 [73] Assignee Deutsche Goldund Silber-Scheideanstalt vormalsRoessler Frankfurt am Main, Germany [32] Priority June 29, 1967 [33]Germany [31] P 15 93 836.0

[54] N-PROPIOPHENONE-NOREPHEDRINES AND SALTS THEREOF 6 Claims, NoDrawings [52] US. Cl ..2 60L5 70. 5 Q, 260/501 1 8, 2150/5676 M, 424/330[51] int. Cl C07c 95/08 [50] Field of Search ..260/501.l8, 570.5 C

[56] References Cited UNITED STATES PATENTS 3,197,507 7/1965 Freed et al260/570.5 3,225,095 12/1965 Thiel 260/570.5 3,337,546 8/1967Malatestinie et a]. 260/570.5 X 3,337,626 8/1967 Thiele 260/570.5

Primary ExaminerRobert V. Hines Attorney-Stephens, Huettig & O'ConnellABSIRACP min k ofthe sztmu R is selected from the group consisting ofBr, lower alkyl, NH,, and trifluoromethyl;

R and R are selected from the group consisting of H, -Cl, Br, loweralkyl, -OH and lower alkoxy;

R is H, methyl or ethyl;

R is H or lower alkyl;

R is H or methyl;

R is H or OH and at least one of R and R is --OH and the other is H, OH,halogen, lower alkyl or lower alkoxy and certain amino ketones of saidformula wherein R, R, R and R are -l-l, R is methyl and R is OH andtheir pharmacologically acceptable acid addition salts and quaternaryammonium salts, such compounds having pharmaceutical activity inimproving the heart function.

NPROPIOPHENONE-NOREPHEDRINES AND SALTS THEREOF BACKGROUND OF THEINVENTION Compounds of the formula R R R R2 R4 0 7 R II wherein:

DESCRIPTION OF THE INVENTION INCLUDING PREFERRED EMBODIMENTS Accordingto the invention, it was found that compounds of the following formula,as well as their pharmacologically acceptable acid addition andquaternary ammonium salts R is selected from the group consisting of Br,lower alkyl, NH and trifluoromethyl;

R and R are selected from the group consisting of H, Cl, Br, loweralkyl, --OH and lower alkoxy;

R is l-I, methyl or ethyl;

R is H or lower alkyl;

R is --I-I or methyl;

R is H or OH and at least one of R and R is OH and the other is I-I, OH,halogen, lower alkyl or lower alkoxy as well as certain compounds ofsuch a formula wherein R R R and R are hydrogen, R is methyl and R" is0I-I also possess valuable properties in improving the heart function.

For sake of simplicity in the following general description of theprocess for preparing the compounds according to the invention, theradical which also appears at the left end of the formula I for thecompounds according to the invention will be designated as Phand theradical (JO (Ill;

It III with a compound of the formula together with formaldehyde or aformaldehyde-yielding substance;

b. reacting a compound of the formula with a compound of the formula inwhich one of Z and W represents halogen and the other NI-IR", in thepresence of a basic substance; c. reacting a compound of the formula orthe corresponding Mannich base R10 Ph C O(I HCH,N B12, R VIII wherein Rand R are lower alkyl with a compound of the formula IV;

d. reacting a compound of the formula PhMe in which Me is alkali metal,MgCl, MgBr or Mgl with a compound of the formula in which V is CN orCOI-Ial (I-Ial=Cl or Br);

e. hydrogenating a compound of formula II in which R is a nitro group soas to reduce this nitro group selectively to the amino group.

In methods a-d, in the event R is an amino group, the amino group in thestarting compound employed is first benzylated, or acylated with anaromatic or aliphatic carboxylic acid or with a carbobenzoxy acid. Theseprotective groups are then subsequently split off by known methods. Thedeacylation of the acylated amino group is preferably carried out in anacid medium, for instance, alcohol/water/acid at temperatures betweenand C. The benzyl radical and the carbobenzoxy radicals can, forexample, be removed by catalytic hydrogenation with palladium catalystsat low temperatures.

In procedure (a) temperatures of 20 to C. are usually employed. Solventssuch as alcohols, dioxane, glacial acetic acid and the like come intoconsideration.

Procedure (b) is usually carried out at elevated temperatures, such as,for example, between 80 and 140 C., in a solvent such as an alcohol,ether, dimethyl formamide and the like. Alkali metal alcoholates, alkalimetal amides, alkali metal carbonates and tertiary amines, for instance,come into consideration as the basic substances.

Procedure (c) when carried out with unsaturated ketone VII is generallycarried out at temperatures between 20 and 80 C. in an inert solvent,such as, ether, acetone, dioxane or chloroform and when carried out withthe corresponding Mannich base Vlll, which during the reactionintermediately decomposes to the unsaturated ketone Vll is generallycarried out at 30 to 120 C. in a solvent such as water, alcohol/water ora two-phase system such as water/benzene or water/toluene.

Procedure (d) is preferably carried out at temperatures between 20 and+80 C. Solvents, such as, ether, dioxane, tetrahydrofurane or benzenecome into question.

The selective reduction of the nitro group in procedure (e) is carriedout by known methods, for example, by hydrogenation in the present of ausual hydrogenation catalyst, such as, palladium, platinum oxide,Raney-nickel, in a solvent, such as, alcohol, preferably at normalpressure at temperatures between 20 and 50 C. or by reduction withnascent hydrogen, for example, reduction with Zn/Hcl, Sn/Hcl, F e/Hcl,activated Al in water containing ether or by reduction with salts of H 8in alcohol/water or reduction with SnCl- HCl The compounds according tothe invention which contain optically active carbon atoms which usuallyare obtained as racemates can be separated into their optically activeisomers or diastereomers by the normal methods. However, opticallyactive isomers or diastereomers can also be used as starting materials.

The compounds according to the invention can be converted to theirpharmacologically acceptable acid addition salts or quaternary ammoniumsalts with the aid of such pharmacologically acceptable acids such asacetic, succinic, maleic, fumaric, lactic, hydrochloric, hydrobromic,sulfuric, phosphoric acids or quaternizing compounds such as the loweralkyl halides.

Conversely, when the acid salts are produced as primary products, theymay be converted to their free base by treatment with a base such aspotassium carbonate.

The compounds according to the invention possess valuable pharmaceuticalproperties and are suited for the treatment of heart and circulatoryconditions and especially for increasing the coronary blood flow incombination with an improvement in the heart function. The compoundswere tested on the isolated guinea pig heart following the method ofLangendorff (Pflugers Arch. 61, 219, 1889) for their activity oncoronary blood flow, contraction amplitude and heart frequency.Metabolism investigations on the Langendorff heart have also shown thatthe increase in contraction amplitude is accompanied by an increasedproduction of energy supplying substrates and improved utilization ofthe latter. Their toxicity LD 50 mgJkg. was tested on mice upon oralapplication by the method of Miller and Tainter (Proc. Soc. exper. Biol.a. Med. 57, 261,1944).

The compounds according to the invention produce a moderate to strongdilation of the coronary system with a simultaneous increase incontraction amplitude in a dosage range of 10-500 ug/heart. Theytherefore are suited for im proving the function of the heart muscle, aswell as the blood flow through the heart muscle.

The administration of the compounds according to the invention is by thestandard modes for administration of compounds which are active inimproving coronary blood circulation, such as, for example, enteral,parenteral, oral or perlingual. The dosage rate upon intravenousadministration to animals, for example, dogs, is in the range of about-50 mg./kg.

The following examples will serve to illustrate the compounds accordingto the invention.

Example 1 l-3-[ 1-phenyl-l-hydroxy-propyl-(2)-amino]-1-(2,4-dimethyl-phenyl)-propanone-( l )-HC1 V CH OH Example 2 1-3-[l-phenyl-1-hydroxy-propyl-(2)-amino]-l-(2,3-dimethyl-phenyl)-propanone-( l )HCl 35.5 g. (0.24mol) of2,5-dimethyl acetophenone were reacted as described in example 1 withl-norephedrine and paraformaldehyde. Yield of HCl salt 36 g., meltingpoint 1791 8 1 C. (recrystallized from ethanol).

Example 3 l-3-[ l-phenyl-1-hydroxy-propy1-(2)-amino]-1-(3,4-dimethyl-phenyl)-propanone-( 1 )'HCl 35.5 g. (0.24 mol) of3,4-dimethyl acetophenone were reacted as describe in example 1 withl-norephedrine and paraformaldehyde. Yield of HCl salt 46 g., meltingpoint 204 205 C. (recrystallized from methanol).

Example 4 l-3-[ l-phenyl-1-hydroxy-propyl-(2)-amino]-1- (4-bromo-phenyl)-propanone-( l )HCl 21.9 g. (0.11 mol) of 4-bromo acetophenone, 15.1 g.(0.1 mol) of l-norephedrine and 3.6 g. (0.12 mol) of paraformaldehydewere added to 60 ml. of isopropanol and the mixture adjusted to a pH of4 with 25 ml. of isopropanolic HCl The mixture was then boiled underreflux for 2 hours whereupon the hydrochloride precipitated out. Yieldof HCl salt 13 g. melting point 203205 C. (recrystallized frommethanol).

Example 5 l-3-[ l-phenyl-1-hydroxy-propyl-(2)-amino1-l-(3-bromo-phenyl)-propanone-( l )'HCl 2 l .9 g. of 3bromo acetophenonewere reacted as described in example 4 with l-norephedrine andparaformaldehyde. Yield of HCl salt 14 g. melting point 21 l210 C.(recrystallized from methanol).

Example 6 l-3-[ 1-phenyl-1-hydroxy-propyl-(2)-amino]- l(3-trifluoromethyl-phenyl)-propanone-( l )-HCl 25 g. (0.133 mol) of3-trifluoromethyl acetophenone, 25 g. (0.133 mol) of l-norephedrine-HCIand 8 g. (0.267 mol) of paraformaldehyde were boiled under reflux for 2hours in ml. of isopropanol. Upon cooling down the HCl salt precipitatedout. Yield of HCl salt 17 g. melting point 2l721 9 C. (recrystallizedfrom methanol).

Example 7 l-3-[ l-phenyll -hydroxy-propyl-( 2 )-amino l(3-amino-phenyl)-propanone-( l )HCl 9 g. (0.0247 mol) of l-3-[l-phenyl-l-l-hydroxy-propyl- (2)- amino]-1-(3-nitro-phenyl)-propanone-(l )HCl (prepared by method (a); U.S. Pat. No. 3,225,095) werehydrogenated in 75 ml. of methanol in the presence of 2.5 g. ofpalladium/barium sulfate (5 percent) whereupon the temperature rose to40 C. The reduction was interrupted after 1.78 liters of hydrogen hadbeen taken up, the catalyst filtered off and the solvent distilled off.Yield 4.5 g. of the monohydrochloride, melting point 162 C.(recrystallized from ethanol).

Example 8 l-3-[ l -pheny1- 1 -hydroxy-propyl-( 2 )-amino]- 1(3-amino-4-hydroxy-phenyl)-propanone-( l 2HC1 15 g. (0.41 mol) of1-3-[1-phenyl-1-hydroxy-propyl-(22)- amino]-1-(3-nitro-4-hydroxy-phenyl)-propanone-( l )-HCl (m.p. 204-205 C. preparedby a method analogous to that for the nitro compound of example 7 werehydrogenated in 500 ml. of methanol in the presence of 1.5 g. ofpalladium/carbon (5 percent) at 50 C. The reduction was interruptedafter 2.76 liters of hydrogen had been taken up, the catalyst filteredoff, the filtrate acidified with isopropanolic HCl and the solventdistilled off. Yield 11 g. of the dihydrochloride, melting point 235-236C. (recrystallized from methanol).

Example 9 1-3-[ l-phenyl-l-hydroxy-propyl-(2)-amino]-1-(2-hydroxy-5-methyl-phenyl)-propanone-( 1 )'HCl 32.4 g. ofZ-hydroXy-S-methyl acetophenone, 6 g. of 5 paraformaldehyde and 27.1 g.of l-norephedrine adjusted to a pH of 3.5 with 1 ml. of isopropanolicHCl were boiled under reflux and processed as in example 6. Afterrecrystallization from methanol the melting point of the HCl saltproduct was 2 l 9-222 C.

Example 10 d, l -3-[ 1-(4-hydroxy-phenyl)- l -hydroxy-propyl- (2)-amino]- l 3-methyl-phenyl)-propanone-( 1 )HC] 15.4 g. (0.1 mol) of3-methyl acetophenone, 3.9 g. (0.13 mol) of paraformaldehyde and 20.3 g.(0.1 mol) of d,1-phydroxy norcphedrine'HCl were heated under reflux for8 hours in 150 ml. of Z-butanol. The solvent was distilled off and theresidue washed twice with ether, then dissolved in isopropanol and theHCl salt precipitated with ether. Yield 21 g. of the hydrochloride salt,melting point 7375 C.

EXAMPLE 1 l d, l -3-[ 1 -(4-hydroxy-phenyl)-1-hydroxy-propyl-(2)-ammo]-1-(3-bromo-phenyl)-propanone-( 1)'HC1 19.9 g. (0.1 mol) of 3-bromoacetophenone, 3.9 g. (0.13 mol) of paraformaldehyde and 20.3 g. (0.1mol) of d,1-phydroxy norepherdrine'l-lcl were heated under reflux for 8hours in 150 ml. of Z-butanol. The solvent was distilled off and theresidue washed twice with 100 ml. of ether and twice with 100 ml. ofwater, then dissolved in acetone and the HCl salt precipitated withether. Yield 6 g. of the HCl salt, melting point 80-84 C.

EXAMPLE 12 l-3-[ 1-phenyl-l-hydroxy-propyl-(2)-amino]-1-(2-methoxy-5-methyl-phenyl)-propanone-( 1 )HCl 13 g. (0.081 mol) ofZ-methoXy-S-methyl acetophenone, 4.5 g. (0.15 mol) of paraformaldehydeand 15.2 g. (0.081 mol) of l-norephedrineX'HC] were boiled under thereflux in 60 ml. of isopropanol for 4 hours. After the reaction solutioncooled acetone and ether were added thereto, whereupon the HCl saltprecipitated out. It was recrystallized from methyl ethyl ketone. Yield9 g., melting point 155-156 C.

I claim:

1. A compound selected from the group consisting of amino ketones oftheformula in which Ph is selected from the group consisting of r i E 713;C F, N111 Nll ()(lll ()ll and their pharamacologically acceptable acidaddition salts.

2. A compound according to claim 1 wherein Ph is 4. A compound accordingto claim 2 where Ph is (b).

5. A compound according to claim 2 where Ph is (c).

6. A compound according to claim 2 where Ph is (d).

2. A compound according to claim 1 wherein Ph is
 3. A compound accordingto claim 2 where Ph is (a).
 4. A compound according to claim 2 where Phis (b).
 5. A compound according to claim 2 where Ph is (c).
 6. Acompound according to claim 2 where Ph is (d).